HIV-1 nef leads to inhibition or activation of T cells depending on its intracellular localization

Baur, Andreas S.; Sawai, Earl T.; Dazin, Paul; Fantl, Wendy J.; Cheng‐Mayer, Cecilia; Peterlin, B. Matija

doi:10.1016/1074-7613(94)90068-x

Cited by 289 publications

(232 citation statements)

References 62 publications

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“…In addition, Nef affects the basal states of T cell activation and the responsiveness of T lymphocytes to TCR signaling (24)(25)(26)(27) with the majority of studies that addressed effects of Nef on distal responses to exogenous TCR stimulation by mitogens or anti-TCR Abs reporting a moderate enhancement by HIV-1 Nef (16,(28)(29)(30)(31)(32)(33)(34). In contrast, HIV-1 Nef severely impairs the formation and organization of IS structures between Nef-expressing T lymphocytes and APCs by reducing the frequency of IS formation, blocking Factin polarization at cell-cell contacts, and inducing mislocalization of the TCR itself as well as its effector kinase Lck (28,(35)(36)(37)(38)(39).…”

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confidence: 99%

HIV-1 Nef Limits Communication between Linker of Activated T Cells and SLP-76 To Reduce Formation of SLP-76–Signaling Microclusters following TCR Stimulation

Abraham

Bankhead

Pan

et al. 2012

The Journal of Immunology

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Signal initiation by engagement of the TCR triggers actin rearrangements, receptor clustering, and dynamic organization of signaling complexes to elicit and sustain downstream signaling. Nef, a pathogenicity factor of HIV, disrupts early TCR signaling in target T cells. To define the mechanism underlying this Nef-mediated signal disruption, we employed quantitative single-cell microscopy following surface-mediated TCR stimulation that allows for dynamic visualization of distinct signaling complexes as microclusters (MCs). Despite marked inhibition of actin remodeling and cell spreading, the induction of MCs containing TCR-CD3 or ZAP70 was not affected significantly by Nef. However, Nef potently inhibited the subsequent formation of MCs positive for the signaling adaptor Src homology-2 domain-containing leukocyte protein of 76 kDa (SLP-76) to reduce MC density in Nef-expressing and HIV-1–infected T cells. Further analyses suggested that Nef prevents formation of SLP-76 MCs at the level of the upstream adaptor protein, linker of activated T cells (LAT), that couples ZAP70 to SLP-76. Nef did not disrupt pre-existing MCs positive for LAT. However, the presence of the viral protein prevented de novo recruitment of active LAT into MCs due to retargeting of LAT to an intracellular compartment. These modulations in MC formation and composition depended on Nef’s ability to simultaneously disrupt both actin remodeling and subcellular localization of TCR-proximal machinery. Nef thus employs a dual mechanism to disturb early TCR signaling by limiting the communication between LAT and SLP-76 and preventing the dynamic formation of SLP-76–signaling MCs.

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confidence: 99%

HIV-1 Nef Limits Communication between Linker of Activated T Cells and SLP-76 To Reduce Formation of SLP-76–Signaling Microclusters following TCR Stimulation

Abraham

Bankhead

Pan

et al. 2012

The Journal of Immunology

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“…Based on numerous observations, Nef appears to play a multifaceted role; it was found to promote high virulence and accelerate viral replication (reviewed in reference 26) and to downregulate cell surface CD4 (47,61) and major histocompatibility complex class I (MHC-I) (35) molecules, as well as to affect T-cell activation (1,3,15,38,62), proliferation (12,36), and cytokine (interleukin-2 [IL-2] and IL-10) production (7,38,67). However, numerous controversial findings have been reported.…”

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confidence: 99%

CD4⁺T Cells from CD4C/HIV^NefTransgenic Mice Show Enhanced Activation In Vivo with Impaired Proliferation In Vitro but Are Dispensable for the Development of a Severe AIDS-Like Organ Disease

Weng

Priceputu

Chrobák

et al. 2004

J Virol

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The cellular and molecular mechanisms of dysfunction and depletion of CD4 ؉ T lymphocytes over the course of human immunodeficiency virus type 1 (HIV-1) infection are still incompletely understood, but chronic immune activation is thought to play an important role in disease progression. We studied CD4 ؉ T-cell biology in CD4C/HIV transgenic (Tg) mice, in which Nef expression is sufficient to induce a severe AIDS-like disease including a preferential decrease of CD4 ؉ T cells. We show here that Nef-expressing Tg CD4 ؉ T cells exhibit an activated/memory-like phenotype which appears to be independent of antigenic stimulation, as documented in experiments involving breeding with AD10 TcR Tg mice. In addition, in vivo bromodeoxyuridine incorporation showed that a larger proportion of Tg than non-Tg CD4 ؉ T cells entered the S phase. However, in vitro, Tg CD4 ؉ T cells were found to have a very limited capacity to divide in response to stimulation with anti-CD3 and anti-CD28 or in allogeneic mixed leukocyte reactions. Interestingly, despite these observations, the deletion of Tg CD4 ؉ T cells had little impact on the development of other AIDS-like organ phenotypes. Thus, the Nef-induced chronic activation of CD4 ؉ T cells may exhaust the T-cell pool and may contribute to the thymic atrophy and the low number of CD4 ؉ T cells observed in these Tg mice.

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“…Nef is critical to the maintenance of a high viral load and for the development of AIDS (2,3). Although the complete function of Nef remains enigmatic, Nef has been shown to enhance viral infectivity and replication in primary cells (4,5), induce down-regulation of CD4 (6, 7) and major histocompatibility complex class I surface expression (8), and alter the activation of T cells (3,9,10). Deletions and mutations in the nef gene have been associated with long-term survival in patients infected with HIV (11,12).…”

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confidence: 99%

Interleukin 10 is induced by recombinant HIV-1 Nef protein involving the calcium/calmodulin-dependent phosphodiesterase signal transduction pathway

Brigino

Haraguchi

Koutsonikolis

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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HIV-1 nef leads to inhibition or activation of T cells depending on its intracellular localization

Cited by 289 publications

References 62 publications

HIV-1 Nef Limits Communication between Linker of Activated T Cells and SLP-76 To Reduce Formation of SLP-76–Signaling Microclusters following TCR Stimulation

HIV-1 Nef Limits Communication between Linker of Activated T Cells and SLP-76 To Reduce Formation of SLP-76–Signaling Microclusters following TCR Stimulation

CD4⁺T Cells from CD4C/HIV^NefTransgenic Mice Show Enhanced Activation In Vivo with Impaired Proliferation In Vitro but Are Dispensable for the Development of a Severe AIDS-Like Organ Disease

Interleukin 10 is induced by recombinant HIV-1 Nef protein involving the calcium/calmodulin-dependent phosphodiesterase signal transduction pathway

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HIV-1 nef leads to inhibition or activation of T cells depending on its intracellular localization

Cited by 289 publications

References 62 publications

HIV-1 Nef Limits Communication between Linker of Activated T Cells and SLP-76 To Reduce Formation of SLP-76–Signaling Microclusters following TCR Stimulation

HIV-1 Nef Limits Communication between Linker of Activated T Cells and SLP-76 To Reduce Formation of SLP-76–Signaling Microclusters following TCR Stimulation

CD4+T Cells from CD4C/HIVNefTransgenic Mice Show Enhanced Activation In Vivo with Impaired Proliferation In Vitro but Are Dispensable for the Development of a Severe AIDS-Like Organ Disease

Interleukin 10 is induced by recombinant HIV-1 Nef protein involving the calcium/calmodulin-dependent phosphodiesterase signal transduction pathway

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CD4⁺T Cells from CD4C/HIV^NefTransgenic Mice Show Enhanced Activation In Vivo with Impaired Proliferation In Vitro but Are Dispensable for the Development of a Severe AIDS-Like Organ Disease